Reviving the Acid Phosphatase Test for Prostate Cancer

ABSTRACT: Prostatic acid phosphatase (PAP) emerged as the world's first clinically useful tumor marker in the 1940s and 1950s. With the introduction of the prostate-specific antigen (PSA) test in the 1980s, which performed significantly better than PAP in terms of screening and monitoring response to treatment, PAP fell into disfavor. An increasing number of recent studies have identified PAP as a significant prognostic factor for patients with intermediate- and high-risk prostate cancer. PAP appears to be particularly valuable in predicting distant failure in higher-risk patients for whom high levels of local control are achieved with aggressive initial local treatment. As prostate cancer care becomes increasingly focused on identifying the minority of patients who would benefit from aggressive systemic therapy, a reevaluation of the potential contribution of the prostatic acid phosphatase test seems timely.

Most prostate cancers are detected at an early stage, and most patients are cured by surgery or radiation. However, nearly 30% of patients with early-stage disease go on to develop biochemical failure, and many of these men will eventually die from hormone-refractory disease.[1,2] In absolute terms, prostate cancer is still the third leading cause of cancer mortality among men in the United States, with an estimated 27,000 deaths in 2006.[2] Thus, while most men are cured by primary treatment, a subset would likely benefit from more aggressive (adjuvant) treatment.

Systemic therapeutic options for prostate cancer are improving.[3] But because adjuvant therapies often entail significant adverse side effects, it is important to identify patients who are most likely to benefit. The use of higher prostate-specific antigen (PSA) levels or higher Gleason scores as criteria for adjuvant therapy is suboptimal for this purpose, because the majority of patients with markedly elevated PSA or Gleason scores are still curable with effective local therapy.[4,5] A number of older and more recent studies suggest that prostatic acid phosphatase (PAP) could play a role in determining which early-stage patients are likely to benefit from more aggressive adjuvant therapy.

Measuring Prostatic Acid Phosphatase

Acid phosphatases are a group of five ubiquitous tissue isoenzymes that hydrolyze organic monophosphate esters. They are present in many human tissues including platelets, lung, osteoclasts, erythrocytes, liver, and kidney.[6,7] However, prostate-specific acid phosphatase is over 100 times more abundant in the prostate than in other tissue types.[8]

Enzymatic reactions using phosphomonoester substrates were developed to measure serum acid phosphatase concentrations. The original tests were unable to differentiate between prostatic and other tissue sources. A variety of techniques were developed to improve sensitivity, such as adding L-tartrate, which somewhat selectively inhibited prostatic acid phosphatase. In 1971, Roy developed what is considered to be the most prostate-specific of the enzymatic reactions utilizing thymolphthalein phosphate.[9]

The enzymatic assays have recognized technical limitations. They are unstable at room temperature, requiring immediate freezing or buffering. There is diurnal and random variability. And there is a low sensitivity for early-stage disease.[9,10] Radioimmunoassays were developed in the 1970s with somewhat greater sensitivity and in vitro specificity, but they are subject to some of the same limitations as the enzymatic tests.[7,10]

A significant perceived limitation of PAP as a cancer marker is the fact that levels can be artificially elevated in the setting of nonprostatic disease or benign conditions of the prostate. Paget's disease, hyperparathyroidism, Gaucher's disease, multiple myeloma, and other malignancies associated with skeletal metastases, prostatitis, and prostatic infarcts can cause increases in serum PAP.[6,11] There are also conflicting reports of prostatic massage leading to transient PAP elevation that returns to normal within 24 to 48 hours. Other research suggests that less aggressive routine digital rectal exams may not cause this transient rise.[6,8] Modest PAP elevations have been identified in a minority of men with benign prostatic hypertrophy (BPH),[12] although this is more common with the radioimmunoassays than the enzymatic tests.[11,13] Overall, the clinical significance of these potentially artificially elevated levels is probably not great, but needs to be better defined.

Pre-PSA Era

FIGURE 1Prostatic Acid Phosphatase Timeline

In 1938, Gutman and Gutman reported increased levels of acid phosphatase in patients with metastatic prostate cancer.[14] Shortly thereafter, Huggins and Hodges[15] discovered that men with prostate cancer treated by orchiectomy or estrogen injections experienced regression of their clinical disease, correlated with a significant decrease in their acid phosphatase levels. These findings formed the foundation of current androgen deprivation strategies. They also established acid phosphatase as a tumor marker for prostate cancer (Figure 1).

From the 1950s through the 1980s, acid phosphatase was widely used to detect, stage, and monitor prostate cancer treatment response, with some success.[8] In 1984, Whitesel and colleagues reported that elevated PAP levels corresponded with a high risk of occult pelvic metastases and subsequent bone metastases.[16] They recommended creating a new clinical stage for prostate cancer (D0) for patients with elevated PAP but no clinical evidence of metastasis. Elevated pretreatment PAP levels were considered to be a relative contraindication to surgery. National Prostatic Cancer Project investigators reported that survival was significantly shorter for patients with elevated acid phosphatase.[17] Several investigators demonstrated that posttreatment PAP could also be used to monitor response to therapy.[18,19] Although PAP proved moderately useful, researchers were interested in finding more sensitive markers that could identify patients at an earlier stage, when disease was curable.

Prostate-specific antigen was first isolated in seminal plasma in 1971. By the 1980s, investigators at the Roswell Park Memorial Institute demonstrated that elevated serum PSA levels were associated with BPH and prostate cancer.[12] PSA was quickly compared against PAP as a prostate cancer biomarker.

Screening With PSA vs PAP

PAP had long been known to have a low sensitivity for diagnosing new disease.[8] Stamey compared PSA to PAP and found a 45% sensitivity for PAP compared to 96% for PSA. PAP sensitivity was particularly low for patients with early-stage disease (0% for stage A, 9% for stage B1).[12] Since the goal of prostate cancer screening is to identify early-stage treatable disease, PAP was rightly dropped as a screening tool.

Staging With PSA vs PAP

In older series from the pre-PSA era, elevated pretreatment PAP had a high specificity for advanced-stage disease. However, PAP's sensitivity for advanced disease was only 50% to 80%,[10,20] meaning that normal serum PAP levels were not accepted as convincing proof of early-stage disease. Staging comparisons of PAP vs PSA showed that the latter was a better predictor of primary tumor volume, extent of capsular penetration and pretreatment clinical stage.[21]

Questions were raised regarding how much additional staging information PAP provided beyond PSA and clinical exam. Johns Hopkins investigators[22] reported that only 4.6% of 460 patients evaluated for prostatectomy had an elevated PAP. All patients with an elevated PAP were found to have extracapsular disease at the time of prostatectomy. However, 81% of patients with an elevated PAP were also identified as having extracapsular spread by either a PSA greater than 100 ng/mL or unequivocal extracapsular extension by digital rectal exam. Hence, PAP provided unique information on only 0.9% of the 460 patients.

In 1987, Stamey et al demonstrated the advantages of PSA over PAP to evaluate and monitor newly diagnosed prostate cancer patients.[12] In 1984, 62% of men worked up for prostate cancer had a PAP serum level drawn vs 5% who had PSA tested. By 1990, only 3 years after the Stamey article, the number of men having PAP included in their initial evaluation was down to 47%, whereas PSA was checked in 66%.[23] By the mid-1990s, serum PAP was declared to have "no practical role in the clinical staging of newly diagnosed prostate cancer."[24]

Monitoring Disease Recurrence

PAP also is clearly inferior to PSA in identifying subclinical disease persistence after prostatectomy or radiation therapy.[10] After prostatectomy, PSA levels nearly always drop to undetectable levels in the absence of residual disease. PAP, on the other hand, commonly remains in the detectable range after prostatectomy, because of other tissue sources. As a result, PAP is not a sensitive marker for residual, subclinical disease.

Clinical recurrence is almost always preceded by a rising PSA. PAP, on the other hand, frequently remains in the normal range, even in the presence of clinically evident metastases. Oesterling and colleagues reported that 100% of patients with clinically evident recurrence had elevated PSA levels, while only 50% had an elevated PAP.[25] National Prostatic Cancer Project investigators reported that almost a quarter of patients with clinically evident metastatic disease had normal PAP.[17]

Demise of PAP

PAP's fall from favor was primarily due to its poor sensitivity for screening or as an indicator of persistent disease. In the process of substituting PSA as a screening and monitoring tool, PAP's strength as a prognostic marker was overlooked. Recently published predictive nomograms and risk categorization models ignore it.[26-29] But PAP may still turn out to be a clinically valuable tool.

Predicting Biochemical Control

FIGURE 2Freedom From Biochemical Failure

FIGURE 3Freedom From Biochemical Failure After Radiotherapy

In contrast to PAP's inferiority in staging and posttreatment monitoring functions, an elevated pretreatment PAP has consistently been identified as a significant prognostic factor.[17,30,31] In the PSA era, Walter Reed investigators studied 295 higher-risk prostatectomy patients. Those with an elevated preprostatectomy PAP had only a 39% 4-year biochemical disease-free survival vs 79% for patients with a normal PAP. Patients with elevated PAP had significantly lower disease-free survival across all PSA levels.[32] Johns Hopkins investigators reviewed 1,600 patients and also identified pretreatment PAP as an independent prognostic factor, with a hazard ratio for biochemical failure similar to that of PSA.[33] The only recent surgical series that did not identify PAP as a predictor of cancer recurrence was one from Beth Israel Deaconess (Figure 2).[34] However, their negative finding was in a homogeneously low-risk population of 180 patients with very few recurrences.

Similar to the surgical series, Dattoli and colleagues reported in 2003 that pretreatment PAP was a stronger predictor of biochemical failure than PSA or Gleason score after palladium (Pd)-103 brachytherapy in 161 higher-risk patients.[35] PAP was particularly useful in stratifying risk level of patients with PSAs between 4 and 20 ng/mL. Recently published long-term follow-up of this cohort confirms the initial findings (Figure 3).[36]